The Herlyn laboratory has a long history of collaborations with members of the Penn/Wistar campus, particularly those who have had an interest in melanoma.
The Program Project on Etiology, Progression and Therapy has been continuously funded since 1980. This Program Project fosters interactions with outside investigators, and coordinates the many related activities that define a Melanoma Research Center. Since 2008, the Program Project on Targeted therapies in melanoma has exemplified the multidisciplinary nature of our research, as the four projects are represented by biologists, immunologists, structural biologists, chemists, pathologists, oncologists and biostatisticians. These programs have supported several critically important resources: 1.) development of more than 400 cell lines from melanocytic lesions of different stages of progression; 2.) MAbs against melanoma-associated antigens; 3.) Biological models of human melanoma; and 4.) Viral vectors for either up regulation of gene expression or knock-down.
The SMR’s principal goal is bringing together members who vary widely in their professions—from basic researchers to translational researchers to clinicians— but share an abiding devotion to improving the lives of those suffering from melanoma through research.
In coming years, with the incorporation of new technologies into experimental and clinical research, we expect rapid advances in cutaneous melanoma prevention, diagnosis and therapy. To bring new technology-based discoveries from bench to bedside and back, we will need to attain a far greater level of cooperation between labs and clinics. In addition, we expect to develop specific inhibitors for metastatic melanoma, rendering it in the next few years a treatable disease.
However, we face major challenges in securing funding, building infrastructure, and gaining expertise in new technologies. To meet these challenges, we will need to form multidisciplinary collaborations. SMR, through yearly congresses, workshops, and its website, will play the role of a catalyst.
The Melanoma Research Foundation (MRF) is the largest independent, national organization devoted to melanoma in the United States. Committed to the support of medical research in finding effective treatments and eventually a cure for melanoma, the MRF also educates patients and physicians about prevention, diagnosis and the treatment of melanoma. The MRF is an active advocate for the melanoma community, helping to raise awareness of this disease and the need for a cure. The MRF's website is the premier source for melanoma information seekers.
Mission Statement: To support medical RESEARCH for finding effective treatments and eventually a cure for melanoma. To EDUCATE patients and physicians about the prevention, diagnosis and treatment of melanoma. To act as an ADVOCATE for the melanoma community to raise the awareness of this disease and the need for a cure.
Melanoma is the deadliest form of skin cancer, and it is one of the cancers whose incidence is increasing fastest in this country. In 2007, melanoma touched the lives of Debra and Leon Black when Debra was diagnosed with the disease. With melanoma incidence rising dramatically and survival for those with advanced disease remaining static at less than 15 percent, the Blacks formed the Melanoma Research Alliance (MRA) under the auspices of the Milken Institute. Thanks to their generous ongoing support, all public donations to MRA go directly to melanoma research. Our ultimate goal is to find a cure by funding the most promising melanoma research worldwide that will accelerate progress and improve outcomes for patients and all who are at risk.
MRA is the largest private funder of melanoma research. To date, MRA has awarded $30 million to 73 research programs to make transforming advances in the prevention, diagnosis, staging, and treatment of melanoma, including research in biological causes of carcinogenesis, skin screening, biomarkers, imaging, immunotherapy, molecularly targeted therapy, and combination therapy.
Collaboration is at MRA's core—from the team approaches to research that we fund, to the way we find partners who can help us realize our vision. Our allies are also focused on increasing public knowledge about the seriousness of melanoma and ways to reduce risk and improve early detection. MRA is pleased to have the generous support of a growing list of corporate allies in the fight against melanoma to amplify our message and garner the resources necessary to advance our mission. Through a unique partnership with Bruce Springsteen and the Danny Fund, MRA has been engaged in a series of public awareness initiatives urging people to protect themselves from the sun's damaging rays, avoid indoor tanning, and be aware of changes in their skin. Together with our allies and your support, we are working toward the day when no one will suffer or die from melanoma.
NDRI is a non-profit, federally-funded organization (click to view funding sources) that was founded in 1980 because of a dream. Lee Ducat, the mother of a diabetic son, became NDRI’s founder and president to help scientists studying diabetes to find a cure.
Back then, obtaining adequate numbers of pancreas for diabetes research was an incredible challenge for most researchers who were forced to rely on their own, local contacts. Scientists voiced their need and with their guidance, the concept of a national human tissue and organ retrieval system became a reality.
Soon, researchers studying other types of diseases and conditions recognized the success of NDRI’s national network. They began to request help in finding human biomaterials for their research projects.
Today, researchers from universities, medical centers and hospitals in just about every major U.S. city rely on NDRI to deliver the specimens they need to advance their studies. Genetic studies are provided with DNA and data on valuable, well-characterized families.
MPIP is the oldest and largest community of people affected by melanoma hosted through the Melanoma Research Foundation. It is designed to provide support and information to caregivers, patients, family and friends. Once you have been touched by melanoma—either as a patient or as a family member or friend of a patient—you become part of a community. It is not a community anyone joins willingly. But if you must be part of this group, you will find no better place to find the tools you need in your journey with this cancer, and the friends who can make that journey more bearable.
The PanAmerican Society for Pigment Cell Research (PASPCR) is a scientific society devoted to those of us interested in various aspects of pigment cells. Our Society is a very interactive one, meeting on an annual basis, and is composed of clinicians, developmental biologists, biochemists, immunologists, cell biologists, molecular biologists, chemists and physicists, among other disciplines. Look at the PASPCR Information Page for more information on our Society.
The International Federation of Pigment Cell Societies (IFPCS) was founded in 1990 to foster interactions in the various disciplines of pigment cell research. The IFPCS was developed initially in 1977 as the International Pigment Cell Society (IPCS) which in turn gave rise to the various regional Pigment Cell Societies that now comprise the IFPCS. Over the years, these groups have sponsored a series of International Pigment Cell Conferences (IPCC) and a summary of those IPCC Conferences, their sites, their Organizers, past recipients of various IFPCS sponsored Awards and past IFPCS Council members are included in this section.
SPORE in Cancer
NIH/NCI Specialized Program of Research Excellence
Funding period: October 2014 through September 2019
The intent of the Penn/Wistar SPORE in Skin Cancer is to decrease the morbidity and mortality of skin cancers through the development of targeted therapies. This SPORE investigates three major skin cancers—melanoma, cutaneous T cell lymphoma (CTCL) and squamous cell carcinoma (SCC). The projects and cores focus on the leading cause of skin cancer deaths, melanoma. Our overarching hypothesis is that maximal long-lasting clinical impact achieved by interfering with signaling pathways and/or stimulating the host immune response requires that we take into account tumor-specific and host-specific genetic and epigenetic signatures. Each of the four projects has clear translational objectives and specific hypotheses that rest on a solid body of preliminary studies. The three cores support the projects and the developmental research and career developmental programs.
The first overall objective is to develop novel therapies in melanoma. In three of the four projects, we propose clinical trials of advanced metastatic melanoma with the overall hypothesis that melanoma is not a homogenous disease and, therefore, should be treated with different strategies. Projects 1 and 2 capitalize on our previous findings that two of the major druggable resistance mechanisms to BRAF inhibition in BRAF-mutant melanoma are activation of PI3K signaling and autophagy. Project 1 (Herlyn/Schuchter) proposes extensive tissue-based studies to understand the effects of concurrently targeting mutant BRAF and PI3K. We expect the combination to be more effective in killing tumor cells and preventing or extending recurrence in a large subset of patients. Project 2 (Amaravadi/Speicher) combines autophagy and BRAF inhibition in patients with BRAF-mutant melanoma, and identifies other effective targeted therapy and autophagy inhibitor combination strategies that have future development potential for BRAF wild-type patients. Project 4 (Vonderheide/Kalos/June) deals with immunotherapy of melanoma by adoptive transfer of lymphocytes that are engineered to bind to tumor cells. The project is built on highly encouraging data from other malignancies that show activated T cells can achieve effective tumor regression and lasting clinical responses.
The second overall objective is to establish new biomarkers in advanced melanoma. We hypothesize that identification of meaningful biomarkers not only will increase our knowledge of the dynamics of disease regression and progression before, during, and after therapy, but also will directly impact the management of the disease by tailored selection of therapy for patients, improved assessment during therapy, and enhanced outcome prediction. In Projects 1 and 2, we will analyze patients' melanomas for genetic abnormalities with the intent of stratifying them prior to initiation of therapy into at least five different disease groups that will dictate therapeutic decision-making. We also will determine whether therapy-related changes can be detected in the sera (Project 2), tumors (Projects 1 and 2), and/or blood (Project 4) of patients. Finally, Project 3 (Nathanson/Kanetsky) is a genome-wide association study that will investigate inherited genetic susceptibility to acute toxicities and outcomes of immunostimulatory therapy using the anti-CTLA4 drug, Ipilimumab. Here we expect to discover novel genetic signatures that may, after further study, facilitate identification of patient subgroups to help tailor therapeutic decision making.
We expect that this highly interactive SPORE program will yield tangible results for clinical practice in melanoma and other cancers of the skin.
The specific goals for this highly interactive program project are summarized below:
Aim 1: Develop effective therapies in melanoma. In three of the four projects we propose clinical trials in patients with advanced melanoma. The overall hypothesis is that melanoma is a complex and heterogeneous disease and therefore should be treated with rationally combinatorial therapeutic approaches. Project 1 proposes a clinical trial of combination therapies for patients with BRAF mutant metastatic melanoma that concurrently targets both the BRAF and PI3K pathways. Project 2 combines an autophagy inhibitor with an inhibitor of mutant BRAF (vemurafenib), addressing the hypothesis that dual therapy will elicit a stronger tumor inhibitory response compared to targeting mutant BRAF alone. This project also will identify effective combinations of targeted therapies with autophagy inhibitors for BRAF wild type/NRAS wild type and NRAS mutant melanoma. Project 4 focuses on immunotherapy of melanoma using adoptive transfer of lymphocytes that are genetically engineered to target tumor cells. This project is built on highly encouraging data from other malignancies that engineered T-cells can achieve effective tumor regression and lasting clinical responses. We expect all three projects to yield critical information to guide further development of new therapies.
Aim 2: Establish effective biomarkers in melanoma. Our group has a long history of defining different steps of tumor progression in melanoma using clinical, histopathologic, genetic, biological, and immunological criteria for each step. In this SPORE application, we focus on advanced, metastatic disease, hypothesizing that integrated and comprehensive biomarker analyses will not only increase our knowledge of the dynamics of disease regression and progression before, during, and after therapy, but also will directly inform and impact management itself. Biomarker development will allow for the tailored selection of therapy for patients, identify which drugs in a given class are most effective, improve assessment during therapy and enhance outcome prediction. Biomarkers also will be used to understand the genetic basis for response to therapy and potential adverse effects of therapy. Thus, we propose to use biomarkers for the following:
i. Patients’ selection for therapy and follow up. Prior to subjecting patients to therapy we will analyze their melanomas for genetic abnormalities and their plasma for circulating biomarkers with the intent of stratifying them into different disease groups that will inform therapeutic decision-making. These analyses are critical for Projects 1 and 2. We will determine whether therapy-related biomarker modulation can be detected in sera (Project 2) and tumors (Projects 1, 2 and 4).
ii. Prediction of adverse events and outcome of the therapy. We will test the hypothesis that inherited genetic variations in part determine the clinical outcome of treatment with immunomodulatory therapy as well immune related adverse events using the anti-CTLA4 drug ipilimumab. These analyses are critical for Project 3.
A. Importance of the proposed translational goals
Melanoma has been one of the fastest rising malignancies in the last four decades with cases increasing from under three per 100,000 people to over thirteen (18.9 in whites). In the United States 76,690 new invasive melanomas and 9,480 deaths from melanoma are expected in 2013. Despite worldwide efforts in prevention, diagnosis, and treatment, the number of new cases of melanoma continues to rise. Until recently, treatment of advanced disease produced cure rates of less than 3%; overall five year survival rates were ~15%1.
Recent successes in melanoma For decades only the immunomodulators interferon-alpha and interleukin-2 and the chemotherapeutic agents dacarbazine (DTIC) and temozolomide were FDA approved. Two new drugs were then approved in 2011. One targets the mutated BRAF kinase, which is found in ~50% of melanomas, while the other targets CTLA-4, which is an inhibitory molecule on T cells. Vemurafenib (Zelboraf) is a small molecule kinase inhibitor that specifically targets mutated BRAF (V600E). It is indicated for the treatment of patients with unresectable metastatic melanoma harboring this mutation. Clinically meaningful, treatment-induced improvements in progression-free and overall survival of patients with metastatic disease have generated tremendous excitement in the field 7-10. Although these results have been very encouraging, nearly all patients treated with vemurafenib eventually progress. It is clear now that the mechanisms of resistance to BRAF inhibitors are heterogeneous with between five to ten distinct mechanisms of resistance now reported in the literature. Therefore it is critical to determine the role of each of these mechanisms both preclinically and clinically in order to optimize personalized therapies for patients with melanoma. Projects 1 and 2 will tackle two of these resistance mechanisms, activation of the PI3K signaling pathway (Project 1) and induction of cytoprotective autophagy (Project 2). Ipilimumab improved overall survival in patients with advanced melanoma compared to gp100 vaccine 11. A second trial found that ipilimumab and DTIC improved survival compared to DTIC alone, confirming the efficacy of ipilimumab12. However, there is a high rate of immune related adverse events with ipilimumab and only 10-20% of patients achieve durable long-term responses. Identifying patients who are most likely to respond (or will have no response) to ipilimumab treatment and/or who are least likely to develop significant toxicity is a critical unmet need that will be addressed by project 3. Additionally, emerging immunotherapies such as anti-PD1 antibody are proving to be effective. Combination therapy with ipilimumab and PD-1 also appears very promising, underscoring the continuing need to understand how to best select patients for ipilimumab-based therapy. Finally, Project 4 in this SPORE proposes using c-Met RNA CAR T cells as a highly personalized approach to immunotherapy, generated with patients own T cells. This represents a distinct and complementary approach to immune checkpoint inhibitors, such as the anti-PD1 antibody and anti-CTLA4 antibodies. These projects therefore address critical unmet needs in melanoma therapy.
1.) Overcoming resistance to BRAF inhibition: The median PFS of patients treated with BRAF inhibitors is approximately seven months. Multiple groups have reported diverse mechanisms of resistance including reactivation of MAPK pathway and, as our group has demonstrated, activation of the parallel PI3K pathway13, 14. Project 1 will address the unmet need of testing combinations that can overcome specific known resistance mechanisms. We have launched the first and largest randomized trial combining a BRAF inhibitor with a potent and specific PI3K inhibitor and will do mechanistic studies to understand determinants of clinical benefit and resistance in parallel preclinical studies. Our studies will provide important information to the rapidly changing field of targeted therapy.
2.) Recent advances in our understanding of the genetics and genomics of melanoma. Within the past year with multiple publications using massively parallel sequencing, and with the rapid availability of the Cancer Genome Atlas (TCGA) data, we have an improved understanding of the genetic and genomics of melanoma. These data are being used to develop a targeted capture, which will be used for massively parallel sequencing of tumors, PDX and cell lines within the Penn/Wistar melanoma program. These reagents are used in Projects 1 and 2.
3.) Improving therapy efficacy for patients with mutant BRAF using autophagy inhibitors in combination with a BRAF inhibitor. Therapy-induced autophagy, a stress-induced survival pathway, is likely a key limitation to the efficacy of agents that target mutant BRAF, and other targeted therapies in BRAF wild type melanoma. Project 2 builds on encouraging clinical activity of combining targeted therapies with autophagy inhibitors.
4.) Selecting patients more effectively for ipilimumab therapy. Identifying host biomarkers of response and of autoimmune toxicity to ipilimumab would prevent unnecessary treatment failures and potentially reduce its sometimes irreversible autoimmune side effects. Given ipilimumab’s substantial toxicity, a key challenge is to identify which patients will derive the most clinical benefit. Project 3 proposes to do an association study that is the necessary first step in identifying clinically useful biomarkers in the host genome.
5.) Identifying more specific immunotherapy modalities to improve cure rates for advanced melanoma.
Anti-CTLA4 is an initial first step in targeting immune checkpoints, and there are rare patients who have complete responses with this therapy. Nevertheless, its effects on T cell stimulation are not confined to tumor specific cytotoxic T cell subsets, and this leads too often to severe autoimmune disease and/or an ineffective immune response. PD-1/PD-L1 mAb, alone or in combination with ipilimumab, also promising but already primary refractory patients are being observed and only a fraction of those responding have a durable response. Adoptive immunotherapy, with chimeric antigen receptor (CAR) engineered T cells, allows for specific targeting of cytotoxic T cells to the tumor microenvironment and represents a novel approach that should be able to augment immune checkpoint antibody therapy. Project 4 proposes the first in human trial in melanoma for this unique approach to immunotherapy that was pioneered at Penn.
B. This SPORE will improve scientific knowledge and change clinical practice in cancers of the skin.
1.) Signaling inhibitors. Soon after the BRAF mutation was discovered in 2002, we began a series of clinical trials with the first generation RAF inhibitor, sorafenib8, 15. Although initial results were disappointing in melanoma, we continued with more specific inhibitors to BRAF, first using tool compounds16, 17, and then the highly selective and potent drug vemurafenib7, 18, 19. The clinical success of the selective BRAF inhibitors provided a sharp inflection point in the field. It is the foundation of Project 1 (Herlyn/Schuchter) and its clinical trial designed to evaluate vemurafenib with PX-866, a PI3K inhibitor. This biospecimen rich clinical trial will test the hypothesis that the addition of a PI3K inhibitor will prevent and/or overcome resistance to BRAF targeted therapy. In addition, this study will provide a unique collection of tumor biopsies, both to validate the presence of described resistance mechanisms and discover novel ones. Concurrently, we are preclinically investigating approximately 50 kinase inhibitors, many of which are being tested in melanoma patients and will be candidates for future clinical trials, mostly as combination therapies.
2.) Autophagy. In addition to using genetic alterations as a guide for therapy, members of our group have been at the forefront of studying the role of autophagy, a process originally considered to be part of the apoptosis machinery for cells, but recently shown to also have an important role in tumor survival20. This observation has led to a number of clinical trials combining an autophagy inhibitor with conventional chemotherapy or, more recently, with signaling inhibitors (Project 2, Amaravadi/Speicher). Our ongoing studies have also led to the development of an improved autophagy inhibitor (Mcafee, Amaravadi et al. PNAS 2012). This we plan to advance towards clinical development, while simultaneously conducting clinical trials with approved drugs. We anticipate that the combination of BRAF and autophagy inhibition will significantly improve melanoma therapy.
3.) Immunotherapy. The Penn/Wistar group has a long history of developing and testing immunotherapy in melanoma, with an established track record of using monoclonal antibodies to target tumor antigens, immunomodulatory agents to modify ant-tumor immunity, and adoptive immunotherapy 4, 6, 21-23. In Project 4 (Vonderheide/June/Kalos) we are building on these long-standing interests to develop antigen-specific, adoptive T cell immunotherapy-based approaches to target malignancies. We anticipate that the adoptive T- cell immunotherapy project outlined in this application will facilitate the development of broader platforms for more widespread clinical application of adoptive therapy to target solid malignancies and our group is expected to be at the forefront of this rapidly evolving field. Project 3 (Nathanson/Kanetsky) addresses one of the most important clinical questions that medical oncologists face: Given the potentially serious adverse immune events associated with treatment, can we identify which patients will benefit from ipilimumab therapy and which patients will have significant toxicity? Project 3 will amass the largest current collection of biospecimens from ipilimumab treated patients. Importantly and in recognition of her stature in the field, Dr.Nathanson has access to biospecimens from national clinical trials with defined response and toxicity endpoints. This study will yield an invaluable data set and resource for current and future studies.
4.) Biomarkers. Our group was among the first to use monoclonal antibodies to identify tumor-associated antigens in melanoma4 and to delineate the different stages of tumor progression24. Although monoclonal antibodies are still of value for biomarker detection, the major emphasis is today and in this application on genome-wide (or at least multiple gene) detection strategies using genetics/genomics and proteomics platforms. Biomarker analysis is a critical component in all four projects. We anticipate that the broad, hypothesis-based approach we propose will generate biomarker candidates that will become part of clinical practice in the therapy of melanoma. We anticipate that the projects we propose will make major contributions to the identification and selection of candidate biomarkers. These biomarkers will in turn be further tested and validated in multi-center collaborations that have already been established and outlined in the Collaboration section. We anticipate that the broad, hypothesis-based approach we propose will generate biomarker candidates that will become part of the clinical practice in the therapy of melanoma.
C. Concepts that drive the translational research in this SPORE.
Four major concepts drive the translational research of this SPORE and they will continue to be of importance as we achieve the aims of our projects and prepare for the next generation of studies.
1.) Targeting melanoma cells with strategies to overcome resistance to BRAF inhibition (Project 1).
In the initial clinical response to BRAF inhibitors we can distinguish two patterns among patients: a strong initial response that is long lasting and a weak response with short progression-free survival. Our preliminary studies, as outlined in Project 1, indicate that PTEN status is associated with predicting response to BRAF inhibitors, pointing to the importance of the PI3K pathway. However, even in cases with wild-type PTEN, not all melanoma cells are killed by vemurafenib and the lack of cell death is associated with the development of acquired or secondary resistance and further activation of PI3K pathway. Acquired resistance has been intensely studied by us and others13, 14. Our preclinical studies suggest that concurrent PI3K and BRAF inhibition synergizes to maximize killing in both PTEN absent and present groups, a finding we expect will have highly significant consequences for BRAF inhibition strategies.
2.) Targeting autophagy inhibition concurrently with targeted therapy (Project 2). Autophagy is a survival mechanism in most cancers but of particular importance for melanoma20, 25, 26, likely related to extensive activation of the anti-apoptotic machinery in melanoma and the close relationship between autophagy and melanosomagenesis27. Targeting mutant BRAF concurrently with autophagy blockade has strong synergistic activities. One of the critical needs to evaluating this approach is measuring effective autophagy modulation in patients to determine which drug is actually impacting the pathway. Our use of proteomics to characterize tumor-secreted biomarkers will have an impact beyond melanoma on the whole field of autophagy inhibition. Identification of targeted therapies whose activity could be significantly improved with autophagy inhibition in NRAS mutant and BRAF/NRAS wild type melanoma is also a major gap in melanoma therapy that this project will address.
3.) Association of therapy outcomes and inherited genetic variation (Project 3). Anti-CTLA4 therapy (e.g., with ipilimumab) is highly effective in approximately 20% of patients but also rather toxic in approximately 20% of patients. These groups are only partially overlapping. Identifying inherited variation using genome- wide association studies (GWAS) associated with response and irAEs could have a considerable impact on clinical practice as it is the first necessary step toward developing a model to determine which patients will derive the greatest benefit and which are at high risk for severe adverse reactions. At this time, ipilimumab is still used as single agent. In the future, we aim to predict which combination therapies with ipilimumab (or its congeners) are best suited to individuals. This work will also be important for combinations with anti-PD-1 and anti-PDL-1 drugs, and Drs. Nathanson and Kanetsky have also garnered strong support from BMS to collaborate on studying inherited variation in this context.
4.) Adoptive immunotherapy (Project 4). There are ample examples of the power of the immune system to effectively control malignancies, including the rejection of tumor masses when the immune response is activated, and the elimination of very large tumor burdens in late-stage patients as recently demonstrated by our group3. In Project 4, we will evaluate in a clinical trial the application of T cells engineered to target the proto-oncogene c-Met on the surface of melanoma cells. In the future, we expect to increase our portfolio of targets in melanoma that are selective for the malignant cells, thus increasing anti-tumor efficacy and decreasing the potential risk of adverse events.